The objective of this project is to provide the most detailed analysis to-date of the impact of the chemical bisphenol A (BPA) on immune system development, and will specifically test the hypothesis that developmental BPA exposure enhances susceptibility to three common immune-mediated diseases later in life. The proposed research is a large-scale project that will improve synergy and interactions among an integrated, multi-disciplinary research team with expertise in toxicology, immunology, immune development, and pulmonary and gastrointestinal diseases. In the 1st Aim a determination of how developmental exposure to BPA affects the development of the immune system will be investigated. The 2nd Aim will use mouse models of asthma, inflammatory bowel disease and infection with influenza A virus to determine how developmental exposure to BPA affects the onset, activity, and resolution of these diseases. Further studies will then probe underlying changes in the function of cellular components of the innate and adaptive immune system, and in the 3rd Aim, an identification of the cellular targets of BPA that lead to increased disease susceptibility using a combination of modern immunological approaches such as bone marrow chimeras, adoptive transfer, and disease-specific functional assays will ensue. Evaluating how BPA impacts the developing immune system in the context animal models of common human diseases will deliver many benefits. First, BPA interacts with receptors that are transcription factors, but the contribution of these interactions to disease are not entirely clear;therefore what is learned will provide new information about how gene-environment interactions influence immune development and function. Second, developmental exposure to BPA likely contributes to other human diseases, and many of the regulatory pathways activated in the model systems we will use are deregulated in other diseases. Given the growing link between pollutants, respiratory infection, and chronic inflammatory diseases, these studies will help delineate the causal basis for these relationships, and may lead to the discovery of common molecular targets of BPA and new strategies to prevent or mitigate environmentally-mediated diseases. Finally, in addition to creating new scientific information, the proposed research will directly advance the objectives of the American Reinvestment and Recovery Act by enabling the hiring of new laboratory staff and the procurement of research reagents and supplies. Thus, this project will have direct, positive impact on the local and national economy. PUBLIC HEALTH RELEVANCE: This research addresses growing concern about how bisphenol A impacts development and contributes to human disease, and will improve our understanding of the potential for bisphenol A to affect the developing immune system and lead to poorer health later in life.